The Program Project is focused on individual differences in cognitive decline and brain aging in hippocampal/cortical systems. All of the work in the application is centered on an animal model of aging, using pathogen-free male Long-Evans rats that are additionally screened to ensure health status. Healthy rats in our study population at 24-25 months of age display an age-related impairment in hippocampal dependent spatial learning with approximately 40-50% of rats at that age falling outsid3e the range of young performance. The participating investigators will deploy their expertise in anatomical, electrophysiological and molecular biological studies of the hippocampus, a system that also supports standardized assessments of cognitive function (Animal Resource Core) for the neurobiological studies. A centralized Data Management Core is designed to facilitate within-project and across-project analyses. The five individual project swill focus on four main program objectives. The first objective will build on our prior studies of structural features of the hippocampal formation in relation to cognitive aging by examining connectional integrity of cortical/hippocampal circuits, gene expression in neurons that are affected in this model (layer II enorhinal cortex and basal forebrain cholinergic neurons), and neurogenesis in the dentate gyrus. The second major objective will involve studies of neural plasticity that will endeavor to link alterations in specific forms of LTP and LTD to age-related cognitive decline and to determine the features of neural encoding in hippocampal/cortical circuits that are directly tied to impairment in cognitive performance. The third major objective will be to identify causes of hippocampal aging. We will pursue a leading hypothesis that oxidative stress is a major factor in brain aging, a hypothesis that is supported by recent data obtained in our model. Further we will examine signaling and transcription pathways that are linked to oxidative stress as well as more systemic sources of stress (AP- 1 glucocorticoid receptors, NFkappaB) and will attempt to link these causal factors in aging to loss of integrity in hippocampal structure/function and cognitive decline. Finally, correlational studies will be supplemented by the use of models that will examine functional outcome with respect to cognition when specific component features of hippocampal aging are reproduced in young adult animals. Our approach has significant potential for increasing our understanding of the aging process and for assessing the therapeutic potential of specific neurobiological interventions.